Technical Field
The present invention relates to systems and methods for the delivery of insoluble or poorly soluble organic compound, such as therapeutic, and/or diagnostic agents. More particularly, the present invention relates to surfactants and surfactant systems used with such compounds.
Background Art
Many organic compounds that are useful in therapeutic or diagnostic applications are poorly soluble or insoluble in aqueous environments. Because of their poor solubility such compounds present challenges to delivering them by traditional administrative routes. Recently, efforts have been made to develop methods and systems whereby such non-soluble and poorly soluble compounds can be delivered to a patient. These efforts have led to the development of different types of drug delivery vehicles.
One approach for delivering poorly soluble or insoluble compounds is to formulate the compound as a solid particle suspension. Compounds that are insoluble in water can be formulated as a stable suspension of sub-micron sized particles in an aqueous medium such as microparticulate or nanoparticulate suspensions. In this way, compounds that were previously unable to be formulated in an aqueous based system can be made suitable for intravenous administration.
Solid particle suspensions of nanoparticles are commonly referred to as nanosuspensions. Nanoparticles range in particle size from about 10 nm to about 10 microns, preferably from about 100 nm to about 2 microns and, more preferably, from about 400 nm to about 1,000 nm. Nanoparticles also are generally coated with or have associated on their surfaces one or more surfactants or other excipients in order to prevent agglomeration, flocculation or what are referred to as Ostwald ripening of the nanoparticles.
Sub-micron sized particles generally and nanoparticles specifically may be administered parenterally. In addition, preparations of small particles of water insoluble compounds may also be suitable for oral, pulmonary, topical, ophthalmic, nasal, buccal, rectal, vaginal, transdermal, or other routes of administration. The small size of the particles improves the dissolution rate of the compound, and hence improves its bioavailability and potentially its toxicity profiles. The particle size will depend on the route of administration, formulation, solubility, and bioavailability of the compound. For example, for oral administration, it is desirable to have a particle size of less than about 7 microns. For pulmonary administration, the particles are preferably less than about 10 microns in size.
One approach for preparing a nanosuspension is described in U.S. Pat. No. 6,607,784, assigned to the assignee of the present application and incorporated herein by reference and made a part hereof. The '784 patent discloses a method for preparing submicron sized particles of an organic compound, wherein the solubility of the organic compound is greater in a water-miscible selected solvent than in another solvent which is aqueous. The process described in the '784 patent generally includes the steps of (i) dissolving the organic compound in the water-miscible selected solvent to form a first solution, (ii) mixing the first solution with a second solvent to precipitate the compound to define a pre-suspension; and (iii) adding energy to the pre-suspension to form particles which can be of submicron size. Often, the average effective particle size can range between about 400 nm to 1,000 nm or below, extending into low micron size, typically no greater than about 2 microns.
Other examples of insoluble compound delivery systems and methods are disclosed in U.S. Pat. Nos. 5,858,410 and 5,922,355. The '355 patent discloses providing submicron sized particles of insoluble compounds using a combination of surface modifiers and a phospholipid, followed by particle size reduction using techniques such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization.
Another approach for providing formulations of insoluble compounds for parenteral delivery is disclosed in U.S. Pat. No. 5,145,684. The '684 patent discloses the wet milling of an insoluble drug in the presence of a surface modifier to provide a particle having an average effective particle size of less than 400 nm. The surface modifier is adsorbed on the surface of the particle in an amount sufficient to prevent agglomeration into larger particles.
In addition to nanoparticulates and nanosuspensions discussed above, other vehicles for delivering insoluble or poorly soluble compounds have also been considered. These include micelles, liposomes, microemulsions, emulsions, nanocapsules, and other dispersed phase (including nanodispersed phase) systems.
Micelles have been considered as vehicles for delivering pharmaceutical components. Micelles are typically spherical structures comprised of a conglomeration of surfactant molecules, formed as a result of the interaction between the hydrophobic parts of the surfactant molecules.
Liposomes have also been considered as vehicles for delivering pharmaceutical components. Liposomes are comprised of a conglomeration of surfactant molecules having one or several bi-layer structures, normally comprising lipid with an aqueous cavity therein. Liposomes possess the capability to incorporate both water-soluble and oil-soluble substances.
Organic compounds such as therapeutic or diagnostic agents may also be delivered in a microemulsion or an emulsion. Microemulsions are bicontinuous structures having only a monolayer wall, comprised generally of water, oil and surfactant(s), (which constitute a single optically isotropic and thermodynamically stable liquid solution.) The size of microemulsion droplets ranges from about 10-100 nm. Microemulsions have the capacity to solubilize both water-soluble and oil-soluble compounds. Accordingly, for delivery, microemulsions can be comprised of oil droplets in an aqueous continuum, water in an oil continuum, or a bicontinuous structures. Other suitable vehicles include cubosomes, which are dispersions of one of the bicontinuous cubic phases that have a lamellar wall, and hexasomes which are dispersions of hexagonal phases that have a lamellar wall.
As noted above, other vehicles for delivering organic compounds such as therapeutic or diagnostic agents are emulsions. Emulsions comprise droplets which are relatively large in size (as compared to microemulsions.) In contrast to microemulsions which form spontaneously, emulsions must be prepared with the input of energy. Formation of emulsions includes high pressure homogenization for producing emulsion droplets (ranging in size from about 100 nm-10 μm) and generating a new surface thereon. Emulsions may be water-in-oil or oil-in-water based on surfactants, oil and water volume fraction, temperature, salt concentration, and the presence of co-surfactants and other co-solutes.
One challenge in the area of insoluble organic compound delivery is that many of the poorly soluble or insoluble compounds, when formulated into submicron sized particles such as nanoparticles, and the like, exhibit undesirable particle growth and/or aggregation (e.g., agglomeration), due in part to the surface activity of the compound. Accordingly, the particle, (emulsion or suspension) may include a selected amount of one or more surfactants that protect the particle form such growth and aggregation, and generally stabilize the particle or other composition and the active ingredient therein.
Surfactants are generally low to moderate weight compounds which contain a hydrophobic portion, which is generally readily soluble in oil, but sparingly soluble or insoluble in water, and a hydrophilic portion, which is sparingly soluble or insoluble in oil, but readily soluble in water. In addition to protecting against growth and aggregation and stabilizing the organic compound delivery vehicle, surfactants are also useful as excipients in organic compound delivery systems and formulations because they increase the effective solubility of an otherwise poorly soluble or non-soluble organic compound, and may decrease hydrolytic degradation, decrease toxicity and generally improve bioavailability. They may also provide selected and advantageous effects on drug release rate and selectivity of drug uptake. Surfactants are generally classified as either anionic, cationic, or nonionic.
Some surfactants suffer from poor physiological compatibility upon injection and/or do not provide effective long term stability. In addition, sub-micron sized particles and other organic compound delivery vehicles that are injected intravenously are often recognized and scavenged by the reticoendothelial system (RES) of the liver, thereby preventing the nanoparticles from being delivered to the target organs.
Thus, it would be desirable to provide a surfactant or combination of surfactants that are effective stabilizers of the submicron sized particles or other organic compound delivery vehicle or system, are safe and physiologically compatible, and protect the particle or other vehicle from being scavenged by the RES of the liver.